Can proteomics help us cure virus latency?

In this episode we talk with Dr Mike Weekes, a clinical consultant and Wellcome Trust Senior Clinical Fellow at the University of Cambridge. Mike visited the CVR a few weeks ago and gave a wonderful seminar about his lab’s work on using a technique he pioneered called ‘quantitative temporal viromics’ (which is a kind of proteomics). They use this method to understand infection by human cytomegalovirus (HCMV – also known as human herpes virus 5) with an overall aim of discovering novel antiviral targets, which are required urgently.

Dr Mike Weekes

HCMV is an incredibly important human pathogen with the majority of people showing evidence of infection. Like other herpes viruses (a diverse group of large DNA viruses), HCMV can cause a chronic, life-long infection, establishing latency within cells throughout your body very easily. Initial infection is associated with a lack of disease with your immune system controlling the virus very well. Despite causing this often silent, life-long infection, HCMV can cause serious disease.

During periods of immunosuppression, the virus may ‘reactivate’, initiating ‘lytic’ replication, which can damage your cells. This can result in severe systemic disease that can affect lots of different organs, such as the liver, retina, large bowel and lung. This is most importantly observed in people suffering with AIDS, young babies and the elderly, as well as those people undergoing organ transplantation who are on immunosuppressive medication. HCMV can cross the placenta (it is a TORCH or CHEAP‑TORCHES pathogen) and infect the unborn child if the mother has a primary infection or suffers a reactivation during pregnancy. This ‘congenital cytomegalovirus infection’ can cause devastating systemic disease in the developing foetus, which can include serious neurological problems.

Despite ongoing research, no vaccines are licensed to date against HCMV and our currently licensed antivirals, which include the famous Ganciclovir, are inhibitors of DNA polymerases (including that of HCMV), only affect actively replicating HCMV (not a latent infection), are associated with toxic side-effects and some HCMV viruses are resistant to them.

The Weekes lab, focuses on identifying and characterising human proteins that can restrict the ability of viruses such as HCMV to replicate. They approach this by accurately measuring the dynamics of host and viral protein expression during an infection over time using ‘quantitative temporal viromics‘.

The clinical potential for this strategy is highlighted in a study published recently that identified one protein, MRP1(a host cellular drug transporter), to be differentially expressed in cells harbouring latent HCMV infection. Latently infected HCMV cells did not express this protein and would accumulate toxic drugs when they were administered. Non-latently infected cells, expressing MRP1, were thus spared. This work presents a strategy to selectively eliminate latently infected cells, which would be of especially great use in an organ transplant setting where you could remove HCMV-infected cells from a donor before giving them to an organ recipient who has never been infected with HCMV.

Listen to the podcast to find more out about Mike, HCMV and his lab’s work.

See below for other CVR science blog posts on herpesviruses include an interview with Professor Peter O’Hare on his work on HSV cell-to-cell spread and innate immunity as well as an award-winning post written by University of Glasgow PhD student Alex Binks on his work on turning herpesviruses in to a safe and effective cancer treatment.

NOTE: this post was edited on 6th March 2016 by request from M. Weekes.

From:The Weekes lab, along with many others, focuses on identifying new HCMV targets for antiviral drug design, including the potential to target cells infected latently.

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“The Weekes lab focuses on identifying and characterising human proteinsthat can restrict the ability of viruses such as HCMV to replicate”